Our long-term objective is to develop a small drug approach for the treatment of Age related Macular Degeneration (AMD) and the related genetic afflictions Stargardt Disease (SD) and Best Disease (BD). AMD is the number one cause of incurable blindness among older adults in the US. Although a palliative therapy is available for wet AMD, there is no treatment available for dry AMD, the most frequent form of the disease (90% of the cases). Growing evidence implicates the abnormal accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) in the pathogenesis of AMD, SD and BD. As LBs are refractory to degradation and RPE cells do not divide, their accumulation in RPE lysosomes progresses with age and is irreversible. Beyond a threshold, LBs cause RPE cell malfunction and death, with consequent death of associated rod and cone photoreceptors. Hence, there is a great need for drugs that remove LBs from RPE. We have recently developed an assay to screen drugs that interact with the major lipofuscin bisretinoid A2E and used this assay to identify a group of A2E-interacting drugs, the cyclodextrins (CD). Our experiments show that some commercial CDs solubilize A2E, prevent its oxidation and reduce A2E levels in cultured RPE cell. Our specific aims are: (1) to test the effectiveness of our leading CDs in preventing retinal degeneration in a mouse model of AMD caused by accumulation of LBs in RPE; (2) to study the mechanism of action of CDs and (3) to develop CDs with increased affinity for LBs and enhanced ability to penetrate RPE lysosomes. These experiments may provide insights on the pathogenesis of AMD and may result in a new kind of drugs to treat dry-AMD, Stargardt Disease and Best Disease, for which no treatment is currently available.